In the first three-year period we completed the primary structure determination of prothrombin (including thrombin), identifying all the vitamin K-dependent modifications. During the second three-year period we determined the primary structures of plasminogen and antithrombin-III; and obtained crystals of the vitamin K-dependent domain from prothrombin which binds Ca++ and phospholipids and of a lysine-binding domain from plasminogen. During the third three-year period we have determine 98% of the primary structure of alpha2-macroglobulin and discovered a thiol ester at its protease-binding site. We have also clarified other aspects of the mechanism by which it inhibits proteinases such as those involved in coagulation and fibrinolysis. Over 55% of the primary structure of fibronectin has been determined, including the domain that binds fibrin and bacterial cells; that which contains the interchain disulfide bridges and is partly phosphorylated; and parts of those which bind gelatin and heparin. Our work on fibronectin has revealed three different sets of multiple internal homologies in this structure until now. In the present project it is proposed to finish the structure work on alpha2-macroglobulin, determine the complete primary structures of fibronectin, protein Z (one of the "new" vitamin K-dependent plasma proteins) and of C1-inactivator (an inhibitor both of complement component C1, and of plasma kallikrein in the early phase of coagulation); to continue work towards solving the tertiary structure of the crystalline prothrombin domain. Knowledge of these protein structures is directly or indirectly important for understanding molecular mechanisms related to thrombosis, fibrinolysis, opsonization, phagocytosis, aspects of malignant transformation, and survival after extensive trauma.